Trauma, inflammation, infection, and aging can cause damages to joint tissues, ultimately leading to arthritic disorders, such as osteoarthritis (OA), septic arthritis, and inflammatory arthritis, resulting in physical disabilities that compromise quality of life; however, no efficacious therapies are currently available. The limited progress in the development of disease-modifying medications (DMMs) is principally because of: (1) insufficient mechanistic understanding of disease onset/progression; (2) inability to encompass the 3-dimensional (3D) and multi-tissue nature of the synovial joint in early phase in vitro drug discovery; and (3) limited utility of pre-clinical animal studies for early stage clinical efficacy and toxicity prediction (lacking ?fail early/fail fast? capabilities), resulting in unanticipated and costly clinical trial failures. Also, patient-specific etiology, progression, and drug sensitivity profiles underscore the need for personalizable therapy development. To address these needs, we propose engineering a 3D human micro-joint chip (mJoint), physiologically analogous to the native joint and capable of modeling pathogenesis of joint diseases for DMM screening/development. UG3 - Aim 1: Engineering joint components The osteochondral complex, synovium, and adipose, will be engineered using primary cells, human mesenchymal stem cells (MSCs) or induced pluripotent stem cell (iPSC) derived MSCs encapsulated in a photocrosslinked hydrogel scaffold, with macrophages included to evaluate their critical function in mediating/regulating inflammation, and phenotype-characterized using molecular, biochemical and histological analyses. Aim 2: Generating normal and diseased mJoint A bioreactor will be designed to house all of the joint elements (mJoint), simulating the respective in vivo tissue conditions, and exposed to various pathogenic agents and conditions to model OA, inflammatory arthritis, and adipose-mediated diabetic joint complications, which will be assessed based on changes in histology and structure in each individual joint component as well as biomarkers. UH3 - Aim 3: Investigating tissue interactions and developing specific biomarkers using mJoint We will assess the contribution of and the interactions among the joint tissue components under normal and diseased conditions. Joint diseases with different etiologies (see Aim 2) will be simulated, tissue interactions analyzed, and potential biomarkers developed to predict joint health. Aim 4: Testing known drugs and screening candidate DMMs We will assess the efficacy of known and candidate DMMs using the mJoint disease models, including interleukin-4, NF-?B decoy oligonucleotides, statins, metalloproteinases inhibitors, and others, focusing also on the applicability of biomarkers identified in Aim 3. Aim 5: Testing potential of cell- based therapy The therapeutic efficacy of human MSCs and their products, such as exosomes and conditioned media, and other biologics, will be examined, in order to explore the scientific basis of the widely perceived utility of stem cell-based therapy for musculoskeletal disorders. In summary, the mJoint represents a high-utility in vitro platform to model synovial joint pathologies and to screen therapeutics for the treatment of joint diseases.